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Review
. 2021 Nov 23:9:780207.
doi: 10.3389/fcell.2021.780207. eCollection 2021.

Mitochondria in Early Forebrain Development: From Neurulation to Mid-Corticogenesis

Ryann M Fame  1 , Maria K Lehtinen  1
Affiliations
Review

Mitochondria in Early Forebrain Development: From Neurulation to Mid-Corticogenesis

Ryann M Fame et al. Front Cell Dev Biol. .

Abstract

Function of the mature central nervous system (CNS) requires a substantial proportion of the body's energy consumption. During development, the CNS anlage must maintain its structure and perform stage-specific functions as it proceeds through discrete developmental stages. While key extrinsic signals and internal transcriptional controls over these processes are well appreciated, metabolic and mitochondrial states are also critical to appropriate forebrain development. Specifically, metabolic state, mitochondrial function, and mitochondrial dynamics/localization play critical roles in neurulation and CNS progenitor specification, progenitor proliferation and survival, neurogenesis, neural migration, and neurite outgrowth and synaptogenesis. With the goal of integrating neurodevelopmental biologists and mitochondrial specialists, this review synthesizes data from disparate models and processes to compile and highlight key roles of mitochondria in the early development of the CNS with specific focus on forebrain development and corticogenesis.

Keywords: corticogenesis; development; forebrain; metabolism; mitochondria; neural tube closure; neurulation.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Early forebrain development: from neurulation to mid-corticogenesis. A developmental timeline outlining the major stages of forebrain development that will be discussed in this review including: neurulation, progenitor expansion, neurogenesis, migration and lamination, and connectivity and synaptogenesis. These drawings are based on mouse brain development.
FIGURE 2
FIGURE 2
Major glucose metabolic pathways. Mitochondria participate in utilization of glucose through the citric acid (TCA) cycle that can then proceed to anabolic pathways using TCA intermediates, or proceed to oxidative phosphorylation through the electron transport chain (ETC) to generate large quantities of energy in the form of ATP. Glucose can be metabolized outside of mitochondria to contribute to glycolysis and the pentose phosphate pathway (PPP).
FIGURE 3
FIGURE 3
Mitochondria changes during neurulation and early neurogenesis. Major metabolic shifts and changes in mitochondria morphology occur throughout neural tube closure (NTC), also known as neurulation. (A,B) As the neuroectoderm of the open neural tube folds to generate neuroepithelium, (C) metabolism shifts away from glycolysis and toward oxidative phosphorylation (OxPhos) along with changes in extracellular and intracellular pH (pHe, pHi) and mitochondrial morphology. Concurrent with this process, chorioallantoic branching further increases oxygen levels (pO2) as development proceeds. Ages are shown for mouse development embryonic days (E) 8.5, E10.5, E12.5. AF, amniotic fluid; CSF, cerebrospinal fluid; ChP, choroid plexus. Scale bar = 1 mm.
FIGURE 4
FIGURE 4
Mitochondrial mobility in cortical progenitors. Mitochondrial mobility is critical for a number of developmental processes during forebrain development. Mitochondrial adaptor proteins couple mitochondria to motor proteins (TRAK and RhoT) that allow transport of the organelles along microtubules. The plus (+) end of microtubules is largely directed to the basal process (Tsai et al., 2010) and kinesin transports generally toward the + end and dynein transports toward the minus (−) end.
FIGURE 5
FIGURE 5
General mitochondrial fission and fusion dynamics. Mitochondrial dynamics include mitobiogeneis, mitochondrial fission/fusion, and mitophagy.
FIGURE 6
FIGURE 6
Mitochondrial dynamics during forebrain neurogenesis. Mitochondrial dynamics and mitochondrial generation reactive oxygen species (ROS) and fatty acid oxidation (FAO) play key roles in maintaining the balance between stemness and terminal differentiation to immature neuron.
FIGURE 7
FIGURE 7
Radial and non-radial migration of immature cortical neurons involve differential mitochondrial mobility. (A) Cortical projection neurons are generated from dorsal (pallial) progenitors and migrate radially along radial glial processes to their location in the developing cortical plate. Early born projection neurons inhabit deeper layers and later-born neurons inhabit more superficial layers generating the cortex in an “inside-out” fashion. Cortical inter neurons are generated in the ventral ganglionic eminences including the lateral ganglionic eminence (LGE), medial ganglionic eminence (MGE), and caudal ganglionic eminence (CGE, not shown). These neurons then migrate non-radially via chain migration into the cortical plate, then migrate radially along radial glial fibers down into the cortical layers. Like projection neurons, early born interneurons inhabit deeper layers and later-born neurons inhabit more superficial layers. (B) Mitochondria are relatively immobile during radial migration residing close to the nucleus on the leading edge of the cell body, while mitochondria in non-radially migrating neurons are highly mobile throughout the leading process and also localized on the lagging edge of the nucleus during retraction of the lagging process. Generally, migration requires high levels of ATP from oxidative phosphorylation.
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